The ras oncogene is activated by mutation, and its translation product Ras protein plays an important role in transformation of normal cells to cancer cells. Such activation of ras oncogene is observed in many cancers such as colorectal cancers or pancreatic cancers, and an proportion thereof is said to reach about 25% of the total human cancers. Accordingly, it is expected that canceration can be suppressed and antitumor effects can be obtained by suppressing such activation of ras oncogene, by inhibiting the function of Ras protein as its product.
Recently, it has been found that farnesyl-modification of Ras protein itself is essential for function of Ras protein, and it is possible to suppress localization of Ras protein at the plasma membrane by inhibiting this farnesyl-modification and thereby to inhibit transformation to cancer cells. The protein-farnesyl transferase (PFT) is an enzyme which catalyses this farnesyl-modification of Ras protein, and by inhibiting this enzyme, it is possible to suppress function of carcinogenic Ras protein. Further, this enzyme contributes to farnesyl-modification of only very limited proteins in vivo. Accordingly, the inhibitor for such an enzyme is expected to be a safe and highly selective antitumor agent. From such a viewpoint, many PFT inhibitors have been developed in recent years (Cell, vol. 57, p. 1167-1177 (1989); Proc. Natl. Acad. Sci., vol. 86, p. 8323-8327 (1989); ditto, vol. 90, p. 2281-2285 (1993); Science, vol. 245, p. 379-385 (1989); ditto, vol. 260, p. 1934-1937 (1993); ditto, vol. 260, p. 1937-1942 (1993); J. Biol. Chem., vol. 266, p. 15575-15578 (1991); J. Antibiotics, vol. 46, p. 222-227 (1993); Japanese Unexamined Patent Publications No. 201869/1993 and No. 213992/1993).
However, up to now, all of the reported PFT inhibitors have had some problems for development as medicines, such that the activities are low in cells, and the effects in vivo are inadequate.